Key result
Blunted CPET heart rate phenotypes linked to ~2.6-fold higher MACE risk in HFpEF.
Why the study?
Conventional definitions of chronotropic incompetence in HFpEF rely on isolated heart rate measurements during CPET. This approach overlooks the dynamic heart rate response during exercise and is affected by submaximal effort, limiting its diagnostic accuracy.
Does time-series clustering of heart rate and oxygen consumption during CPET identify chronotropic response phenotypes that predict major adverse cardiovascular events and higher H2FPEF scores in patients with HFpEF?
Cohort (n=341)
Yes
Does time-series clustering of heart rate and oxygen consumption during CPET identify chronotropic response phenotypes that predict major adverse cardiovascular events and higher H2FPEF scores in patients with HFpEF?
Time-series clustering of CPET heart rate and oxygen consumption identifies distinct blunted chronotropic response phenotypes in HFpEF patients that independently predict a 2.65-fold higher risk of major adverse cardiovascular events and higher H2FPEF scores.
May aid HFpEF risk stratification via CPET phenotypes; extends chronotropic incompetence data but leaves open prospective validation.
Background/Introduction Chronotropic incompetence (CI) is prevalent in patients with heart failure with preserved ejection fraction (HFpEF) and has been linked to adverse events. These associations were derived from a definition of CI based on one or two isolated, often peak, heart rate (HR) measurements during cardiopulmonary exercise testing (CPET). This simple approach overlooks the dynamic character of the HR response during exercise and is affected by submaximal effort, limiting its diagnostic accuracy. Purpose To identify distinct HR response phenotypes in patients with HFpEF using time-series clustering of age-adjusted HR and oxygen consumption (VO2/kg) during CPET, and to evaluate their associations with conventional CI metrics, clinical characteristics including beta-blocker (BB) therapy, H2FPEF scores, and the prediction of major adverse cardiovascular events (MACE). Methods We retrospectively analysed data from 341 individuals with HFpEF (stage A–C) who completed a CPET (RER ≥ 1.05) in two Belgian centres. For both the increase in HR and the change in VO2/kg, age-adjusted residual time series were generated using regression models (y = a + b·time + c·age). These residuals were clustered using dynamic time warping with k-medoids. Clusters were compared on conventional CI measures, clinical characteristics, H2FPEF scores, and the incidence of MACE (heart failure hospitalisation, acute coronary event, or cardiovascular death) during a median follow-up of 3 years (IQR 2.3, 4.1). Results Four HR response phenotypes were identified, ranging from an adequate chronotropic response (cluster 1) to a markedly blunted response (cluster 4) (Figure 1). The clusters did not differ in sex or resting HR and only minimally in age. Cluster 1 showed the highest cardiorespiratory fitness (CRF, % predicted VO2max), the lowest BB use and the most favourable conventional CI parameters. Compared to clusters 1 and 2, clusters 3 and 4 had worse conventional CI parameters, a flatter HR–VO2 slope and were characterized by a higher BMI (Figure 2). Assignment to clusters 3 or 4 was associated with higher H2FPEF scores, independent of BB use, obesity (BMI ≥ 30) and CRF (p = 0.008). Over a median follow-up of 3 years, 29 MACE occurred. Belonging to cluster 3 or 4 independently predicted MACE after adjustment for age, sex, BB use, obesity, and CRF (HR 2.65, p = 0.018, Harrell's C = 0.781). Conclusion Using this time-series analysis of CPET data distinct HR response phenotypes can be identified in patients with HFpEF. This approach offers a more comprehensive evaluation of chronotropic response than conventional single-point CI measures. Phenotypes with the weakest chronotropic response exhibited worse conventional CI parameters, higher HFpEF risk profiles, and an increased risk of adverse events, highlighting the potential clinical value of this complete assessment of chronotropic response for HFpEF assessment and risk stratification.Figure 1Figure 2
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Vermeiren et al. (2026) conducted a cohort in Heart failure with preserved ejection fraction (HFpEF) (n=341). Blunted heart rate response phenotypes (clusters 3 or 4) on time-series CPET clustering vs. Adequate/less blunted heart rate response phenotypes (clusters 1 or 2) was evaluated on Major adverse cardiovascular events (MACE: heart failure hospitalisation, acute coronary event, or cardiovascular death) (HR 2.65, p=0.018). Blunted HR response phenotypes (clusters 3 or 4) on CPET time-series clustering independently predicted MACE in HFpEF patients (adjusted HR 2.65, p=0.018, Harrell's C=0.781).
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